Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia

Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. Although the etiology of preeclampsia is still unclear, recent studies suggest that its major phenotypes, high blood pressure and proteinuria, are due in part to excess circulating soluble fms-like tyrosine kinase-1 concentrations. Soluble fms-like tyrosine kinase-1 is an endogenous antiangiogenic protein that is made by the placenta and acts by neutralizing the proangiogenic proteins vascular endothelial growth factor and placental growth factor. High serum soluble fms-like tyrosine kinase-1 and low serum free placental growth factor and free vascular endothelial growth factor have been observed in preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia but also antedate clinical symptoms by several weeks. Therefore, this raises the possibility of measuring circulating angiogenic proteins in the blood and the urine as a diagnostic and screening tool for preeclampsia. The availability of a test to predict preeclampsia would be a powerful tool in preventing preeclampsia-induced mortality, especially in developing nations, where high-risk specialists are limited. This review will summarize our current understanding of the role of circulating angiogenic proteins in the pathogenesis and clinical diagnosis/prediction of preeclampsia.     

Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension

Recent in vitro studies have reported that heme oxygenase 1 (HO-1) downregulates the angiostatic protein soluble fms-like tyrosine kinase 1 from placental villous explants and that the HO-1 metabolites CO and bilirubin negatively regulate endothelin 1 and reactive oxygen species. Although soluble fms-like tyrosine kinase 1, endothelin 1, and reactive oxygen species have been implicated in the pathophysiology of hypertension during preeclampsia and in response to placental ischemia in pregnant rats, it is unknown whether chronic induction of HO-1 alters the hypertensive response to placental ischemia. The present study examined the hypothesis that HO-1 induction in a rat model of placental ischemia would beneficially affect blood pressure, angiogenic balance, superoxide, and endothelin 1 production in the ischemic placenta. To achieve this goal we examined the effects of cobalt protoporphyrin, an HO-1 inducer, in the reduced uterine perfusion pressure (RUPP) placental ischemia model and in normal pregnant rats. In response to RUPP treatment, mean arterial pressure increases 29 mm Hg (136±7 versus 106±5 mm Hg), which is significantly attenuated by cobalt protoporphyrin (118±5 mm Hg). Although RUPP treatment causes placental soluble fms-like tyrosine kinase 1/vascular endothelial growth factor ratios to alter significantly to an angiostatic balance (1.00±0.10 versus 1.27±0.20), treatment with cobalt protoporphyrin causes a significant shift in the ratio to an angiogenic balance (0.68±0.10). Placental superoxide increased in RUPP (952.5±278.8 versus 243.9±70.5 relative light units/min per milligram) but was significantly attenuated by HO-1 induction (482.7±117.4 relative light units/min per milligram). Also, the preproendothelin message was significantly increased in RUPP, which was prevented by cobalt protoporphyrin. These data indicate that HO-1, or its metabolites, is a potential therapeutic for the treatment of preeclampsia.     

Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy

Imbalances in circulating angiogenic factors contribute to the pathogenesis of preeclampsia. To characterize levels of angiogenic factors in pregnant women with chronic hypertension, we prospectively followed 109 women and measured soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin, and placental growth factor at 12, 20, 28, and 36 weeks' gestation and postpartum. Superimposed preeclampsia developed in 37 (34%) and was early onset (<34 weeks) in 9 and later onset (≥34 weeks) in 28. Circulating levels of sFlt1 and the ratio of sFlt1 to placental growth factor were higher before clinical diagnosis at 20 weeks' gestation in women who subsequently developed early onset preeclampsia between 28 and 34 weeks compared with levels in women who never developed preeclampsia (P=0.001) or who developed late-onset preeclampsia (P=0.001). Circulating levels of sFlt1, soluble endoglin, and the ratio of sFlt1:placental growth factor were also significantly higher, and placental growth factor levels were significantly lower at the time of clinical diagnosis of superimposed preeclampsia in women with either early or late-onset superimposed preeclampsia compared with levels at similar gestational ages in those with uncomplicated chronic hypertension. We conclude that alterations in angiogenic factors are detectable before and at the time of clinical diagnosis of early onset superimposed preeclampsia, whereas alterations were observed only at the time of diagnosis in women with late-onset superimposed preeclampsia. Longitudinal measurements of angiogenic factors may help anticipate early onset superimposed preeclampsia and facilitate diagnosis of superimposed preeclampsia in women with chronic hypertension.     

The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: early- versus late-onset pre-eclampsia

The pathogenesis and aetiology of pre-eclampsia (PE) is still unclear. We investigated the role of angiogenic, antiangiogenic and vasoactive factors in black South African women with early- and late-onset PE. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), soluble vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were determined using the ELISA technique, and placental mRNA expression levels of sFlt-1, VEGF, PlGF and AT1 receptors were determined using real-time PCR. Serum sFlt-1 levels were significantly elevated and PlGF significantly reduced in early-onset PE compared to the normotensive group. Placental VEGF mRNA expression levels were significantly reduced in the late-onset preeclamptic group compared with the normotensives. The placental mRNA expression of AT1 receptor in the late-onset pre-eclamptic group was relatively raised compared to the normotensives, suggesting hypersensitivity to pressor agents. We believe that the excess of serum sFlt-1 and reduced VEGF and PlGF levels favour an anti-angiogenic state and endothelial dysfunction leading to PE, and that the aetiology and pathogenesis of early- and late-onset PE differ.     

Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression

The balance between proangiogenic and antiangiogenic factors, such as vascular endothelial growth factor, placental growth factor, and soluble fms-like tyrosine kinase-1 (sFlt-1), is altered in preeclampsia, and this dysregulation of angiogenic factors may be important in the pathogenesis of preeclampsia. Although sFlt-1 is elevated in preeclampsia, the mechanisms responsible for increasing this antiangiogenic factor remain unclear. We hypothesized that the hypertension produced by reduced uterine perfusion pressure (RUPP) is associated with increased sFlt-1 expression and decreased plasma vascular endothelial growth factor and placental growth factor concentrations in the pregnant rat. Arterial pressure was increased (130+/-3 versus 100+/-2 mm Hg; P<0.01) in the RUPP rats compared with the normal pregnant control rats. Plasma sFlt-1 concentration (660+/-270 versus 82+/-26 pg/mL; P<0.05) was increased, whereas plasma free placental growth factor (0.28+/-0.05 versus 1.7+/-0.5 pg/mL; P<0.01) and vascular endothelial growth factor (594+/-34 versus 830+/-33 pg/mL; P<0.01) concentrations were decreased in the RUPP rats compared with normal pregnant rats. Plasma sFlt-1:placental growth factor (37.2+/-7.8 versus 8.9+/-1.6; P<0.02) and sFlt-1:vascular endothelial growth factor (0.86+/-0.22 versus 0.28+/-0.06; P<0.05) ratios were increased in the RUPP rats compared with normal pregnant rats. Immunoreactive placental sFlt-1 was increased (1.1+/-0.1 versus 0.3+/-0.1; P<0.01) in RUPP rats contrasted with the normal pregnant rats. These findings support our hypothesis that RUPP increases the expression of sFlt-1 and alters the balance of angiogenic factors in the maternal circulation. These data also indicate that the RUPP model of pregnancy-induced hypertension may provide an invaluable model for mechanistic studies into the role of sFlt-1 in the pathogenesis preeclampsia.     

Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion

Angiogenic factors like placental growth factor and its antiangiogenic antagonist soluble fms-like tyrosine kinase 1 (sFlt1) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction. Because it is known that altered maternal sFlt1 and placental growth factor levels are detectable weeks before the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. This prospective study includes 63 second trimester pregnant women with abnormal uterine perfusion. Twenty five of them developed a later complication (12 with preeclampsia, 11 with intrauterine growth restriction, and 2 with intrauterine death), whereas 38 had a normal course of pregnancy. Pregnancies with adverse pregnancy outcome showed in the second trimester significantly higher sFlt1 (1403.6+/-555 versus 451.8+/-42 pg/mL; P<0.05) and lower placental growth factor (139.6+/-24 versus 184.1+/-21 pg/mL) levels compared with those with normal outcome. These alterations were more pronounced in pregnancies with subsequent preeclampsia compared with intrauterine growth restriction and early onset diseases (delivery <34 weeks) compared with late-onset diseases. The combination of Doppler and sFlt1 increases the sensitivity of Doppler alone for iatrogenic preterm delivery from 64% up to 79% and the specificity from 63% up to 80%. Using both factors, sFlt1 and placental growth factor, early onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. We conclude that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early onset pregnancy complications, particularly preeclampsia.     

Molecular mechanisms of preeclampsia

Preeclampsia is a major cause of maternal, fetal and neonatal mortality worldwide. The mechanisms that initiate preeclampsia in humans have been elusive, but some parts of the puzzle have begun to come together. A key discovery in the field was the realization that its major phenotypes, such as hypertension and proteinuria, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). More recently, soluble endoglin, another circulating anti-angiogenic protein was found to synergize with sFlt-1 and contribute to the pathogenesis of preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia, but also antedate clinical symptoms by several weeks. This review will summarize our current understanding of the molecular mechanism of preeclampsia, with an emphasis on the recently characterized circulating anti-angiogenic proteins.     

Correlation between soluble endoglin, vascular endothelial growth factor receptor-1, and adipocytokines in preeclampsia

CONTEXT: Recent reports have demonstrated that soluble endoglin (sEng), an antiangiogenic protein thought to impair TGF-beta binding to receptors, and soluble vascular endothelial growth factor receptor (sVEGFR)-1 play important roles in the pathophysiology of preeclampsia (PE). Moreover, insulin resistance, which is greatly influenced by adipocytokines, characterizes PE. OBJECTIVES: We examined possible links between sEng, VEGF, sVEGFR, and adipocytokines in the pathophysiology of PE. STUDY DESIGN: We performed a cross-sectional study in 30 PE patients and controls matched for gestational age and body mass index. Blood samples were collected soon after disease onset. We measured serum concentrations of leptin, adiponectin, sEng, VEGF, placental growth factor (PlGF), and sVEGFR [soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble fetal liver kinase 1 (sFlk-1)], and examined the placental protein content of sEng and sFlt-1. RESULTS: sEng concentrations in PE patients (60.9 +/- 28.8 ng/ml) were significantly higher than those in controls (11.2 +/- 4.4 ng/ml). There was a significant correlation between sEng and sFlt-1 or PlGF. Moreover, there were significant differences in mean blood pressure between the high and low sEng groups, and in proteinuria between the high and low sFlt-1 groups, and significant differences in placental sEng and sFlt-1 contents between patients with and without severe hypertension or proteinuria. sEng was also correlated positively with adiponectin levels and negatively with the leptin to adiponectin ratio. CONCLUSIONS: Along with sFlt-1 and PlGF, sEng might play a role in the pathophysiology of PE, especially in elevating blood pressure, while the association with hypoadiponectinemia and the high leptin to adiponectin ratio in pregnancy seem to be risk factors for PE.     

Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.

Vascular endothelial cell growth factor, a mitogen selective for vascular endothelial cells in vitro that promotes angiogenesis in vivo, functions through distinct membrane-spanning tyrosine kinase receptors. The cDNA encoding a soluble truncated form of one such receptor, fms-like tyrosine kinase receptor, has been cloned from a human vascular endothelial cell library. The mRNA coding region distinctive to this cDNA has been confirmed to be present in vascular endothelial cells. Soluble fms-like tyrosine kinase receptor mRNA, generated by alternative splicing of the same pre-mRNA used to produce the full-length membrane-spanning receptor, encodes the six N-terminal immunoglobulin-like extracellular ligand-binding domains but does not encode the last such domain, transmembrane-spanning region, and intracellular tyrosine kinase domains. The recombinant soluble human receptor binds vascular endothelial cell growth factor with high affinity and inhibits its mitogenic activity for vascular endothelial cells; thus this soluble receptor could act as an efficient specific antagonist of vascular endothelial cell growth factor in vivo.     

Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model

Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment.     

Molecular determinants of microvascular dysfunction in hypertensive pregnancy and preeclampsia

Preeclampsia is a pregnancy‐related disorder characterized by hypertension and often fetal intrauterine growth restriction, but the underlying mechanisms are unclear. Defective placentation and apoptosis of invasive cytotrophoblasts cause inadequate remodeling of spiral arteries, placental ischemia, and reduced uterine perfusion pressure (RUPP). RUPP causes imbalance between the anti‐angiogenic factors soluble fms‐like tyrosine kinase‐1 and soluble endoglin and the pro‐angiogenic vascular endothelial growth factor and placental growth factor, and stimulates the release of proinflammatory cytokines, hypoxia‐inducible factor, reactive oxygen species, and angiotensin AT₁ receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, smooth muscle and various components of the extracellular matrix. Generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels causes decreases in endothelium‐derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor, and increases in vasoconstrictors such as endothelin‐1 and thromboxane A2. Enhanced mechanisms of vascular smooth muscle contraction, such as intracellular Ca²⁺, protein kinase C, and Rho‐kinase cause further increases in vasoconstriction. Changes in matrix metalloproteinases and extracellular matrix cause inadequate vascular remodeling and increased arterial stiffening, leading to further increases in vascular resistance and hypertension. Therapeutic options are currently limited, but understanding the molecular determinants of microvascular dysfunction could help in the design of new approaches for the prediction and management of preeclampsia.     

Soluble Fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus

OBJECTIVE: Placental synthesis of soluble Fms-like tyrosine kinase (sFlt-1) is responsible for the increased level of serum sFlt-1 in preeclampsia. sFlt-1 binds to the receptor-binding domain of placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), acting as an endogenous inhibitor of VEGF and PlGF signaling in endothelial cells. It has been hypothesized that increased circulating sFlt-1 contributes to the endothelial dysfunction, hypertension, and proteinuria of preeclampsia. We examined the association of sFlt-1 and preeclampsia in pregnancies in patients with systemic lupus erythematosus (SLE). METHODS: A case-control study was performed using stored serum samples. Cases were SLE pregnancies with later preeclampsia and controls were SLE pregnancies without later preeclampsia. RESULTS: The 52 SLE pregnancies occurred from 1998 to 2001. Nine (17%) pregnancies met the definition of preeclampsia and an additional 9 (17%) met the definition of superimposed preeclampsia. sFlt-1 concentration was significantly higher in SLE pregnancies with preeclampsia (1768 +/- 196 pg/ml) than in those without (1177 +/- 143 pg/ml) (p = 0.0185). CONCLUSION: Our study shows for the first time that sFlt-1 is associated with preeclampsia in patients with SLE, as previously shown in the general pregnancy population. This suggests that SLE pregnancies at risk for preeclampsia can be identified early in the pregnancy by sFlt-1, thus identifying them for high-risk obstetric referral and appropriate monitoring.     

An overview of recent advances in pathogenesis and diagnosis of preeclampsia

Preeclampsia is a serious complication of pregnancy, which is the cause of 60 000 maternal deaths annually worldwide. In addition to the well-known maternal risk factors such as hypertension, diabetes mellitus, antiphospholipid antibody syndrome, obesity, aging, and multiple pregnancies, recent studies have identified the role of genetic and immunological factors in the pathogenesis of preeclampsia. In particular, imbalance between angiogenic and anti-angiogenic factors, anti-angiotensin II type 1 receptor antibodies and dysregulation of oxygen supplies can cause preeclampsia. A group of biomarkers have been introduced for diagnosis of preeclampsia. Chief among them is the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor, which can be used in clinical practice. Recent studies have shown high specificity and sensitivity of these markers for early diagnosis of preeclampsia, which is critical for prevention of fetal and maternal complications.     

Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.     

Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia

Sufficient cytotrophoblast (CT) invasion into the uterine wall and subsequent remodeling of maternal uterine vasculature is critical to establish uteroplacental circulation. The production of vascular endothelial growth factor (VEGF) family molecules is confirmed in placental cells including CTs, but it is not elucidated how the VEGF system in CTs is controlled by oxygen tension and how it is involved in the development of placental circulation. To address this, we explored the effect of oxygen tension on the expression of VEGF, placenta growth factor (PlGF), and their antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1) using ELISA and real-time PCR in a primary CT cell culture. For comparison, the same was conducted in parallel using other cells comprising placenta, such as human umbilical vein endothelial cells (HUVECs) and villous fibroblasts (VFs). Reduced oxygen resulted in a pronounced increase in sFlt-1 mRNA amount and sFlt-1 release into the culture media in CTs, whereas this was not the case with HUVECs and VFs. Free (not bound to sFlt-1) VEGF was not detected in CT culture media regardless of oxygen concentration, even though VEGF expression was stimulated by reduced oxygen in CTs, which was similar to the stimulation in HUVECs and VFs. Free PlGF was also diminished in CT culture media by reduced oxygen. These results implicate that CTs possess a unique property to enhance sFlt-1 production under reduced oxygen, which could consequently antagonize angiogenic activity of VEGF and PlGF. The presented findings might provide a framework with which to understand the mechanism of uterine vascular remodeling and its perturbations as exemplified in preeclampsia.     

Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences

Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in the VEGF family may explain the defective uteroplacental vascularization characterizing preeclampsia. We compared pregnancies complicated by early onset severe preeclampsia or intrauterine growth retardation to normal pregnancies. Maternal plasma, placentas, and placental bed biopsies were collected. The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds. Levels of VEGF-A, PlGF, and soluble VEGF receptor (VEGFR) were assessed in maternal plasma. In compromised pregnancies, elevated levels of VEGF-A and VEGFR-1 mRNAs may reflect the hypoxic status of the placenta. On contrast, the membrane-bound VEGFR-1 was decreased in the placental bed of preeclamptic patients. Preeclampsia was associated with low levels of circulating PlGF and increased levels of total VEGF-A and soluble VEGFR-1. Free VEGF-A was undetectable in maternal blood. Immunohistochemical studies revealed that VEGF-A and PlGF were localized in trophoblastic cells. Altogether, our results suggest two different pathophysiological mechanisms associated with preeclampsia. The first one is related to an overproduction of competitive soluble VEGFR-1 that may lead to suppression of VEGF-A and PlGF effects. The second one is the down-regulation of its membrane bound form (VEGFR-1) in the placental bed, which may result in the defective uteroplacental development.     

Soluble vascular endothelial growth factor receptor-1 (sFLT-1) mediates downregulation of FLT-1 and prevents activated neutrophils from women with preeclampsia from additional migration by VEGF

Neutrophil activation and increased migration is associated with preeclampsia and is resolved after delivery. Preeclampsia is an inflammatory disorder where altered levels of vascular endothelial growth factor (VEGF) and the circulating soluble fms-like tyrosine kinase 1 (sFlt-1) have a pathogenic role. VEGF, by binding to FLT-1, induces leukocytic chemotaxis. We studied expression and function of FLT-1 in maternal neutrophils during preeclampsia and normal pregnancies. Analysis of maternal neutrophils showed the relationship between FLT-1 expression and week of gestation. Preeclamptic women express lower FLT-1 and sFLT-1 in neutrophils. In contrast, serum levels of sFLT-1 in patients with preeclampsia are increased and, therefore, inhibit upregulation of FLT-1 in neutrophils by neutralizing VEGF. VEGF-dependent FLT-1 expression is regulated by changing FLT-1-promoter activity. Promoter activity is decreased by sFLT-1. In vitro experiments demonstrated that migration of neutrophils is regulated by VEGF via FLT-1 and excess of sFLT-1. Thus, VEGF-dependent migration of neutrophils is decreased during preeclampsia as a consequence of excess circulating sFlt1. But, they still increase migration by fMLP and, therefore, migration of neutrophils from preeclamptic women is highly activated when compared with the normotensive group. In conclusion, besides being involved in inducing an antiangiogenic state in the serum, excess of sFLT-1 seems to prevent activated neutrophils from women with preeclampsia from additional migration by VEGF. We provide evidence that neutrophils may be involved in the pathophysiology of pregnancy-related hypertensive disorders.     

Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia?

Preeclampsia is a heterogeneous syndrome affecting 3% to 5% of all pregnancies. An imbalance of the antiangiogenic and proangiogenic factors, soluble receptor fms-like tyrosine kinase 1 and placental growth factor (PGF), is thought to contribute to the pathophysiology of preeclampsia. Maternal plasma PGF and soluble receptor fms-like tyrosine kinase 1 were quantified by specific immunoassays in cross-sectional samples from 130 preeclamptic subjects and 342 normotensive controls at delivery and longitudinally in samples from 50 women who developed preeclampsia and 250 normotensive controls. Among women who developed preeclampsia, 46% (n=23) evidenced a pattern of consistently low maternal PGF across pregnancy below the lower 95% CI of controls from 15 weeks' gestation to term. In contrast, the remaining 54% (n=27) of women who developed preeclampsia had maternal PGF concentrations similar to or above (n=7) those of normotensive controls. Subjects with low PGF across pregnancy who developed preeclampsia evidenced significantly higher blood pressure in early pregnancy (P<0.05) and, after diagnosis, earlier gestational age at delivery (P<0.05) and more preterm birth (P<0.05) compared with preeclamptic patients with high PGF. A significant subset of women who develop preeclampsia show evidence of consistently low PGF across pregnancy. Low PGF with preeclampsia was associated with preterm delivery compared with preeclamptic patients with high PGF. Identifying women with consistently low plasma PGF during pregnancy may provide a greater understanding of preeclampsia pathophysiology and may provide more focused research and clinical activities.     

Endothelial nitric oxide synthase deficiency reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant mice

Preeclampsia is associated with impaired uteroplacental adaptations during pregnancy and abnormalities in the endothelial NO synthase (eNOS)-NO pathway, but whether eNOS deficiency plays a causal role is unknown. Thus, the objective of the current study was to determine the role of eNOS in the mother and/or conceptus in uteroplacental changes during pregnancy using eNOS knockout mice. We quantified uterine artery blood flow using microultrasound, visualized the uteroplacental vasculature using vascular corrosion casts, and used pimonidazole and hypoxia-inducible factor 1α immunohistochemistry as markers of hypoxia in the placentas of eNOS knockout mice versus the background strain, C57Bl/6J (wild type). We found that increases in uteroplacental blood flow, uterine artery diameter, and spiral artery length were reduced, and markers of placental hypoxia in the junctional zone were elevated in late gestation in eNOS knockout mice. Both maternal and conceptus genotypes contributed to changes in uterine artery diameter and flow. Despite placental hypoxia, placental soluble fms-like tyrosine kinase 1 and tumor necrosis factor-α mRNA, and in maternal plasma, soluble fms-like tyrosine kinase 1 were not elevated in eNOS knockout mice. Thus, our results show that both eNOS in the mother and the conceptus contribute to uteroplacental vascular changes and increased uterine arterial blood flow in normal pregnancy.